The development of novel approaches to the treatment of non-melanoma skin cancer is of significance. Non-melanotic skin cancers are by far the most prevalent malignancy in the US, comprising about half of all other cancers combined. Basal cell carcinomas (BCCs) are the overwhelming majority of skin malignancies. Our experience and that of others shows that ALA-PDT can have efficacy comparable to ordinary surgery and is advantageous in the skin because it provides enhanced selectivity, outstanding cosmesis, and the option of treating multiple lesions and large surface areas, particularly for nevoid BCC syndrome (NBCCS) patients or those with complex or multiple lesions. However it has reduced overall efficacy, can be painful and relatively ineffective for thick lesions. Therefore the overall goal of this project is to understand the underlying mechanisms in order to improve the efficacy of ALA-PDT, without compromising its selectivity and cosmetic benefits. In the current funding period we have shown, that recurrence basal cell carcinoma (BCC) can be minimized by high light doses at high irradiances, and that PDT treatment efficiency can be greatly improved and pain virtually eliminated at low irradiances. This has led to the hypothesis that elucidation of the low irradiance fluence-tumor response relationship is critical for optimizing efficacy of PDT. PDT can be compromised by vasospasm that locally limits oxygenation, and by inhomogeneous distributions of photosensitizer within the tumor. We hypothesize that examination of perfusion and intra-tumor vascular and photosensitizer distributions is critical for choosing appropriate treatment strategies, understanding mechanisms and constructing computational models for PDT. In collaboration with Project III, we have demonstrated for the first time that PDT enhances patient immune reactivity to a BCC-associated tumor antigen. Pre-clinical studies in Project III have shown that PDT enhanced anti-tumor immunity can be further augmented by addition of an immune modulating agent. We hypothesize that ALA-PDT induced immune responses improve clinical outcomes and can be augmented by the addition of immune modulators, and that vaccination with PDT-treated cells will treat existing BCC and prevent new carcinomas. Finally, we have shown that PDT efficacy can be improved in pre-clinical models through the addition of agents that potentiate effects of oxidative intracellular damage and inhibit tumor growth. We hypothesize that these agents will also improve clinical outcomes with topical and systemic photosensitizers.